NDT Advance Access originally published online on April 17, 2009
Nephrology Dialysis Transplantation 2009 24(7):2018-2020; doi:10.1093/ndt/gfn713
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The plasticity of progenitor cells—why is it of interest to the nephrologists?
Department of Medicine IV, University of the Saarland, Homburg/Saar, Germany
Correspondence and offprint requests to: Ferdinand H. Bahlmann; E-mail: ferdinand.bahlmann{at}uniklinikum-saarland.de
Keywords: cardiovascular disease; chronic kidney disease; endothelial dysfunction; endothelial progenitor cells; regeneration
It is increasingly recognized that chronic kidney disease (CKD) goes in parallel with hypertension and several metabolic disorders such as dyslipidaemia, insulin resistance and hyperuricaemia [1]. These traditional as well as a variety of non-traditional cardiovascular risk factors contribute to accelerated vascular disease resulting into fatal clinical endpoints such as myocardial infarction, cerebro-vascular insults and/or ischaemic events of the lower limbs, which are the most important causes of morbidity and mortality in patients with CKD. In a meta-analysis related to CKD and cardiovascular disease in over 500 000 patients from all continents except Africa, the European Uraemic Toxin work (EUTox) group reported an increased risk of cardiovascular morbidity and mortality when the creatinine clearance falls below 
75 mL/min/1.73 m2 [2]. These findings underline the tremendous risk of patients to suffer from vascular disease even in the early stages of CKD. The search for novel therapeutic strategies to improve the outcomes for these patients is therefore one of the key issues in contemporary renal research. In this respect, endothelial dysfunction plays a central role as the critical precursor of vascular disease in patients with CKD. However, since the kidney with its enormous arterial as well as venous vascular beds has one of the largest endothelial surface areas among solid organs, it is not surprising that recent experimental work highlights the importance of (micro)vascular injury and rarefaction also as a crucial event leading to renal tissue ischaemia and progression of CKD. As a consequence, preserving endothelial and hence vascular integrity may not only prevent cardiovascular events in CKD patients but could also represent a valuable tool for arresting progression.
Endothelial cells within different (renal) vascular beds are exquisitely placed to respond to any form of signals like endocrine or paracrine hormones, cytokines and growth factors as well as to exogenous and endogenous toxins including traditional and non-traditional vascular risk factors. In addition, the endothelium is perfectly situated to sense and to respond to any rheological and haemodynamic changes. Better understanding of how endothelial dysfunction happens is therefore pivotal. Healthy endothelium is characterized by an intact nitric oxide synthase/nitric oxide (eNOS/NO) system, where NO acts both as an intracellular and extracellular messenger mediating normal endothelial and vessel wall function (e.g. antithrombosis, endothelial permselectivity, vasomotor tone, suppression of smooth muscle cell proliferation and quenching of inflammation) [3,4]. In this respect, we and others could show that levels of asymmetric dimethylarginine (ADMA), the endogenous inhibitor of eNOS, are elevated and act as an independent predictor of mortality and even of progression in patients with CKD [5,6]. Moreover, oxidative stress and inflammation are the two major forces driving endothelial dysfunction and vascular injury in CKD patients. Vascular risk factors commonly associated with CKD provoke oxidative stress through activation of NAD(P)H-oxidase and generation of superoxide radicals. Enhanced cellular superoxide traffic—in CKD patients also resulting from activation of angiotensin II receptors—promotes premature cell senescence and apoptosis and thus impairs endothelial homeostasis. As a result, damaged endothelial cells detach.
Traditionally, it was thought that such damaged and detached mature endothelial cells are replaced by neighbouring cells that spread into the injured endothelial area, but the idea that postnatal neo-vascularization results exclusively from remodelling through completely differentiated endothelial cells has been revised by recent findings showing that endothelial progenitor cells (EPCs) from several sources may contribute to vascular repair and even regeneration [7]. It is likely that these processes are also of importance in the long-term evolution of vascular adaptation of patients with CKD. Thus, EPCs could be an ideal tool for vascular and hence also for renal tissue regeneration, since experimental data demonstrated that infusion or injection of stem/progenitor cells improves heart function after myocardial infarction, or enhances blood flow in models of peripheral ischaemia [8]. However, the concept and the success of cell-based therapy are still challenged due to apparent difficulties in assuring good manufacturing practice (GMP)-compliant cell isolation procedures [9]. Although a considerable plasticity of bone-marrow-derived stem cells and/or mesenchymal stem cells could be demonstrated in some experimental models or renal injury so far [10–12], only very low numbers of stem/progenitor cells could be detected in the recovered organs, pointing to the possibility that paracrine growth factor release by these cells is more important for orchestration of the regenerative process than their incorporation to areas of tissue injury [13]. Moreover, as indicated by experimental studies so far, the in-vivo transdifferentiation capacity of stem/progenitor cells into various renal tissues seems to be very limited. As a result, alternative ways to improve vascular repair and regeneration in CKD patients must be explored, with EPC biology and plasticity coming more and more into the focus of interest.
We and others could recently identify abnormalities in EPC number and function in CKD patients compared to age and gender matched controls [14–16]. A significant correlation between CD34+ haematopoietic stem cells and EPCs could be detected in renal patients pointing to a problem of EPC differentiation or to reduced mobilization of EPCs from its niches, or both, in uraemia [14]. Whereas factors contributing to EPC dysregulation in CKD patients are poorly understood, recent experimental work revealed that their regenerative capacity might be impaired by the same factors that also mediate vascular injury. For example, we could show that the in vivo re-endothelialization capacity of EPCs is markedly impaired in patients with type 2 diabetes mellitus as a result—at least in part—of increased NAD(P)H-oxidase-dependent superoxide production and subsequently reduced NO bioavailability [17]. Such data are not yet available for CKD patients, but related mechanisms are plausible in view of similar vascular risk factors present in these two populations. Interestingly, reduced EPC function in uraemic patients was ameliorated by initiation of dialysis or by kidney transplantation [14,15], pointing to the possibility that at least some of the pathophysiologically relevant factors influencing EPC differentiation and function may be inherent to the state of uraemia.
Another way to improve the regenerative capacity of EPCs in CKD patients could be by targeted pharmacological intervention. Indeed, in several explorative clinical trials under different clinical conditions such as uraemia, diabetes mellitus and essential hypertension, administration of pharmaceutical agents such as human recombinant erythropoietin [18], angiotensin receptor blockers [19], peroxisome proliferator-activated receptor (PPAR)-gamma agonists [17] or statins [20] improved both the number and the functional capacity of EPCs. Such pharmacological ‘targeting’ of EPCs may be of considerable interest in future studies related to cardiovascular morbidity and mortality, and even to progression in patients with CKD. However, in order to achieve optimal endothelial and hence vascular repair, and to preserve organ function, we have to better understand the mechanisms by which these drugs act on regenerative cells. Moreover, in view of the recently documented remarkable plasticity of these cells, we also have to better characterize different subpopulations and explore potential differences in their regenerative potential and behaviour. For example, several investigators recently demonstrated the existence of subpopulations of circulating regenerative cells that obviously have different responsibilities in the process of vascular repair and regeneration [21]. While some cells seem to be directly involved in the replacement of damaged and detached endothelial cells, others are likely to drive the process of neo-angiogenesis providing the fundament for new vessel formation, and thus for whole organ regeneration. Only a subset of EPCs was identified as ‘real’ progenitors that give rise to a cell line that repopulates the mature endothelial cell pool [21].
A cell type that is also rapidly gaining importance in the field of regenerative medicine is the multipotent mesenchymal stromal cell (MSC). Previously, these cells have been described as ‘mesenchymal stem cells’, but since there is no proof that MSCs are clonal, self-renewing stem cells, they have been renamed [22]. MSCs can be expanded in vitro and it is thus not difficult to obtain large numbers of these cells for clinical use. In addition, they possess immuno-modulatory properties [23], and allogeneic MSCs do not induce a proliferative T-cell response. Given the importance of inflammatory processes in the pathophysiology of progressive renal injury [24], the immuno-modulatory effects of MSCs may be of relevance [25].
The kidney is an organ with a low rate of cellular turnover under physiologic conditions, but capable of a very high rate of cell proliferation and repair after acute injury. Until recently it was assumed that tubular cells themselves are the source of nephron repair [26]. Moreover, results of several experimental studies demonstrated that endogenous bone-marrow-derived cells or exogenously administered MSCs do not directly replace renal epithelia to a significant extent during the renal repair process, and it became clear that such regeneration is rare and not the primary physiologic mechanism for nephron regeneration. Nevertheless, several lines of evidence indicate that exogenously administered MSCs home to sites of injury, modulate the repair process and thereby ameliorate renal injury [10–12]. The exact molecular and cellular mechanisms that are responsible for the protective and regenerative effects of MSCs are still incompletely understood, but increasing evidence suggests that the primary means of repair by these cells most likely involves paracrine and endocrine factors [27] that mediate mitogenic, antiapoptotic, anti-inflammatory and angiogenic responses. Interestingly, Lange et al. [11] administrated exogenous MSCs labelled with iron-dextran to rats following ischaemia-reperfusion-injury. They could locate these cells using magnetic resonance imaging primarily in the renal cortex, both into glomerular and peritubular capillaries. Either location may be efficacious to promote repair of injured renal epithelial cells: peritubular MSCs may signal to adjacent tubular epithelial cells, whereas glomerular MSCs may secrete factors that are filtered into the tubular lumen, where they may directly regulate and/or facilitate proliferation of damaged epithelial cells.
An alternative action of bone-marrow-derived MSCs could be the activation of an endogenous kidney stem cell population. In a number of studies such cells were isolated from adult kidney; they expressed stem cell markers and incorporated into the renal epithelium after injury [28,29]. Interestingly, when renal tissue-derived CD133+ cells were cultured in vitro with VEGF, they expressed endothelial markers. Further, after injection of these cells subcutaneously into Matrigel, they were reported to form vessels that connected to the endogenous mouse vessels. When injected into mice with acute kidney injury, these cells homed to the kidney and integrated into proximal and distal tubules [29]. So far, in preliminary human trials no major adverse effects have been reported with injection of MSCs. Nevertheless, little long-term follow-up information about the fate of administered MSCs is available. In a recent study, Kunter et al. [30] injected MSCs intrarenally in a rat model of glomerulonephritis. Although they observed a beneficial therapeutic effect, about 20% of the glomeruli in MSC-treated animals contained large adipocytes derived from mal-differentiation of MSCs with pronounced surrounding fibrosis after 2 months of follow-up.
In summary, endothelial dysfunction in patients with CKD relevant to their cardiovascular morbidity on the one hand and to progression on the other hand may be counteracted by stimulation of endothelial and hence vascular repair/regeneration. Two options are likely to be pursued in the future: targeted pharmacological interventions in order to improve EPC dysregulation and cell therapy using precisely characterized regenerative cell subpopulations. For the latter approach, MSCs can be injected that accelerate functional repair of injured nephrons, most likely through paracrine mechanisms. Nevertheless, the physiologic significance and long-term risks, particularly mal-differentiation and/or untoward transformation, are currently unclear. In this respect, the considerable plasticity of (circulating) regenerative cells represents a challenge that has to be explored before targeted (renal) vascular regeneration will become a realistic therapeutic option.
Conflict of interest statement. None declared.
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[Abstract/Free Full Text]
Accepted in revised form: 26.11.08
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